Cardiac muscle is an excitable tissue composed, inter alia, of electrically excitable cardiac muscle cells. Typically, upon intrinsic or artificial supra-threshold electrical excitation cardiac muscle cells generate an action potential which triggers a delayed contraction. Cardiac muscle cells are electrically coupled enabling the flow of currents between them. Normally, a group of pacemaker cells located at the Sino-Atrial node (SA node) generates rhythmic electrical activity in the form of cell depolarization which then spreads rapidly to the rest of the heart, first to the atria and then to the ventricles. The currents flowing from the depolarized pacemaker cells to the neighboring electrically coupled cardiac muscle cells cause a depolarization therein. When the depolarization reaches a threshold value the muscle cells will generate an action potential which will then similarly spread to other coupled muscle cells.
Some of the currently held theories of the ionic basis of cardiac muscle cell action potentials and of the spread of electrical excitation and contraction within the cardiac muscle tissue are disclosed in detail in PCT application, International Publication Number WO 97/25098 to Ben-Haim et al., titled "ELECTRICAL MUSCLE CONTROLLER", incorporated herein by reference.
Reference is now made to FIG. 1 which is a schematic graph illustrating the various phases of a typical transmembrane action potential (TAP) recorded intracellularely in a ventricular cardiac muscle cell in-vitro using a prior art intracellular electrode. Typically, The cell membrane is impaled using a suitable glass microelectrode and the electrical potential difference between the intracellular milieu and an extracellular reference electrode is recorded as a function of time. The vertical axis represents the potential difference between the inside and the outside of the cell and the horizontal axis represents time. The curve labeled 1 represents the TAP signal. Typically, the potential difference across the resting cell membrane also known as the "resting potential" is approximately -90 millivolts (mV). The resting phase 2 lasts until the cell is activated. The minus sign indicates that the cell's inside is negatively charged with respect to the cell's outside. If the potential difference is changed to a value more positive than the resting potential, the cell membrane is the to be depolarized.
When an activation signal such as a localized depolarizing current flows into the cell, the cell membrane locally depolarizes. If the local depolarization reaches a certain threshold value (The action potential threshold), the entire cell membrane will rapidly depolarize within a few milliseconds to a value of approximately +20 mV. This phase is the rapid depolarization phase 4. The cell then repolarizes by about 10 mV in a first repolarization phase 5. The cell then slowly repolarizes by about 20 mV over a period of approximately 200-300 milliseconds, called the plateau phase 6. During the plateau phase 6, the muscle contraction occurs. At the end of the plateau phase 6, the cell continues to repolarize in a rapid repolarization phase 8. Finally, the cell again reaches the resting potential of the resting phase 2.
In the beating heart, this cycle repeats at a rate which is coupled to the intrinsic rate of activation of the cardiac pacemaker cells. During the plateau phase 6 and the rapid repolarization phase 8, the cardiac muscle cell enters a state during which the action potential threshold is modified. This state is called a refractory period. The refractory period includes an absolute refractory period in which the cell cannot be re-excited by a depolarizing stimulus, regardless of the level of the stimulus. The absolute refractory period is followed by a relative refractory period in which the stimulus level required to elicit an action potential is larger than the stimulus level required to elicit an action potential during the resting phase 2. It is possible to experimentally assess the duration of the absolute and relative refractory periods in vitro by injecting depolarizing current pulses through the intracellular electrode at different times during the plateau phase 6 and the fast repolarization phase 8 to determine at which time point re-excition can occur and generate an action potential. The time point at which no stimulus however strong can evoke an action potential will indicate the transition point between the absolute and the relative refractory points.
The cardiac effective refractory period (ERP) is an empirically determined value, generally defined as the time interval between the time of initiation of activation of an excitable cardiac cell or group of cells and the time at which this cell or group of cells can be reactivated by an electrical stimulus of specific predetermined characteristics. The ERP value is therefore stimulus specific. For example, a first reactivating stimulating pulse having a specific set of shape and duration parameters and a specific pulse amplitude value will have a first empirically determined ERP value, while a second reactivating stimulating pulse having the same set of parameters and an amplitude higher than the amplitude of the first stimulating pulse may have a shorter empirically determined second ERP value.
It is noted that, the reference numbers of the various cardiac TAP phases of FIG. 1 are arbitrarily chosen and are not necessarily equivalent to the common terminology used in the medical literature for describing various phases of the cardiac TAP.
Some of the parameters of the TAP such as, inter alia, the action potential duration (APD), the action potential amplitude and the ERP may have significant clinical relevance in assessing various cardiac pathological conditions and the effects of various cardioactive drugs on cardiac tissue. Unfortunately, the technique of microelectrode intracellular recording is currently limited to isolated in-vitro preparations and cannot be clinically used in human patients.
However, other techniques are available which permit use of extracellularly recorded waveforms from the in situ beating heart of patients. Such extracellularly recorded waveforms may provide information related to some of the clinically relevant parameters of the cardiac action potential. One such method is the method of in-situ recording of cardiac monophasic action potentials (MAPs) from the beating heart of a patient.
The article titled "METHODS AND THEORY OF MONOPHASIC ACTION POTENTIAL RECORDING" by Michael R. Franz, in Progress In Cardiovascular diseases, Vol. XXXIII, No. 6. Pp. 347-368, 1991, incorporated herein by reference discloses apparatus and methods for recording of cardiac MAPs in excised tissue and isolated heart preparations in-vitro and in experimental animals and human patients in-vivo, and discusses theoretical aspects of MAP generation.
Cardiac MAPs may be measured by differential recording from two separate electrodes. The first electrode is usually placed in proximity to or in contact with intact cardiac tissue, such as the epicardium or the endocardium and serves as a reference electrode. The other electrode, sometimes referred to as the "probe electrode" is placed in contact with or in close proximity to the cardiac tissue at or near a site of a damaged portion of the tissue which serves as a localized site of injury currents or a site in which injury-like currents are locally induced. The injury-like currents may be generated, among others, by applying negative pressure to the endocardium or epicardium through a suction electrode or by gently pressing a special contact electrode against the endocardium or epicardium as disclosed in detail by Franz in the above referenced article.
Reference is now made to FIG. 2 which is a graph schematically illustrating the shape of a cardiac MAP signal recorded using a prior art contact electrode. The vertical axis represents the amplitude of the extracellularly recorded signal and the horizontal axis represents time. The curve labeled 11 represents the MAP signal. As seen from FIG. 2, the MAP signal is somewhat similar but not identical in shape to the TAP signal. The dashed line 14 represents the potential difference level recorded prior to contact of the sensing electrode with the tissue and is arbitrarily assigned a null value of zero millivolts. Typically, after the sensing electrode contacts the tissue, the recorded potential difference drops until it stabilizes at a new resting level which is the MAP baseline 12.
The precise tissue and cellular events underlying MAP generation are not fully understood. The current hypothesis based on available data, disclosed by Franz in the above referenced article, assumes that mechanical pressure or suction exerted against the myocardium depolarizes and inactivates the group of cells subjacent to the probe electrode, while leaving the adjacent cells largely unaffected.
Because these adjacent normal cells retain their ability to depolarize and repolarize actively, there is an electrical gradient between the depolarized and unexcitable cells subjacent to the electrode and the adjacent normal cells. During electrical diastole, this gradient results in a source current emerging from the normal cells and a sink current descending into the depolarized cells subjacent to the MAP sensing electrode. Under the volume conductor conditions provided by the surrounding tissue and blood pool, the sink current near the MAP sensing electrode results in a negative electrical field that is proportional to the strength of current flow, which again is proportional to the potential gradient between the subjacent depolarized and the adjacent non-depolarized cells. During electrical systole, the normal cells adjacent to the MAP sensing electrode undergo complete depolarization which overshoots the zero potential by some 30 mV whereas the already depolarized, and therefore refractory, cells subjacent to the MAP sensing electrode cannot further depolarize and maintain their potential at the former reference level. As a result, the former current sink reverses to a current source, producing an electrical field of opposite polarity. The strength and polarity of the boundary current and the resulting electrical field reflect the potential gradient between the reference potential in the depolarized and refractory cells subjacent to the electrode and voltage changes in the normal adjacent cells undergoing periodic depolarization and repolarization. According to this hypothesis, the MAP recording reflects the voltage time course of the normal cells that bound the surface of the volume of cells depolarized by the contact pressure.
As disclosed in detail in the article by Franz referenced hereinabove, it was shown by simultaneous recording of TAPs and MAPs from the same isolated rabbit cardiac tissue that there is a close agreement in the general shape and duration of the TAP and MAP signals. While not all the parameters of the MAP signals can be used to assess the underlying TAP parameters, some of the TAP parameters such as the APD, ERP and the repolarization time course may be obtained by measuring corresponding MAP parameter values.
A number of highly relevant clinical applications for the measurement of cardiac Monophasic Action Potentials (MAP) have been proposed. For example, MAP recordings have been used, inter alia, for assessing myocardial viability, monitoring myocardial drug absorption and the effects of anti-arrhythmic drugs on APD, evaluating of atrial and ventricular arrhythmia, determining the effects of heart rate and rhythm on APD, detecting myocardial ischemia, mapping infarcts and other clinical applications.
Methods and devices for the measurement of MAP signals are known in the art. U.S. Pat. No. 5,398,683 to Edwards et al. discloses a combination catheter for detecting monophasic action potential and for ablating surface tissue in an in vivo heart.
U.S. Pat. No. 4,682,603 to Franz et al. discloses a probe having a reference electrode and a probe electrode for recording monophasic action potentials from an in vivo heart.
U.S. Pat. Nos. 4,955,382 and 4,979,510 to Franz et al. disclose probes having a reference electrode, a probe electrode and including a stylet for recording monophasic action potentials from an in vivo heart.
U.S. Pat. No. 4,690,155 to Hess discloses a compartmentalized contact electrode catheter for recording monophasic action potential.
U.S. Pat. No. 5,425,363 to Wang discloses a plunge electrode for recording multiple intramyocardial monophasic action potentials.
U.S. Pat. No. 5,022,396 to Watanabe discloses a catheter for simultaneously measuring monophasic action potentials and endocardiac cavity pressure.
A disadvantage of the in vivo use of the suction electrode method in human patients is that it is typically limited to short duration recordings lasting only a few minutes. This time limitation is mainly due to the danger of causing tissue injury and traumatizing the cardiac muscle by the suction electrode but is also exacerbated by the increased risk to the patient caused by the necessity to use a complicated valve system for controlling the application of negative pressure to the suction electrode resulting in a danger of releasing air bubbles into the cardiovascular circulation which may cause arterial embolism.
The contact electrode method disclosed by Franz et al. in the above referenced Article and in U.S. Pat. Nos. 4,682,603, 4,955,382 and 4,979,510 hereinabove, enables extending the clinically useful MAP recording time to a period lasting up to a few hours. However, extending the MAP recording time beyond a few hours is problematic.
One major reason for the difficulty of extending the recording time beyond a few hours stems from the nature of the cellular processes occurring in the excitable tissue. The injury-like currents and depolarization induced in the group of cells subjacent the probe electrode by the electrode pressure eventually lead to the electrical uncoupling of the depolarized group of cells from adjacent, electrically active muscle cells. While the reasons for this electrical uncoupling are not fully understood, it is believed that the uncoupling is at least partly due to changes in the electrical conductivity properties of the gap-junctions coupling the cardiac muscle cells. Such gap-junction changes may be triggered by the continued presence of injury-like currents and/or the extended depolarization in the cells. Accumulation of Calcium ions and protons may play a role in these changes.
Irrespective of the exact underlying mechanisms, the electrical uncoupling between the cells subjacent the contact electrode and the rest of the cells gradually modifies the currents flowing between the depolarized tissue and the adjacent non-depolarized tissue, resulting in a continuing change of the recorded MAP signals. Typically, during extended recording periods, MAP amplitudes decrease and MAP shape changes over time. This inherent instability and the accompanying distortion of the MAP signal morphology precludes the recording of stable clinically interpretable MAP signals over periods longer than a few hours.
In addition to the problem of electrical uncoupling, when extended recordings of MAPs in vivo are attempted by chronically implanting MAP recording devices such as leads and catheters, other problems interfering with the extended stable recording of MAP signals may include the formation of scar tissue and/or connective tissue in the area of contact between the electrode tip and the tissue. Such tissue changes, referred to as "electrode encapsulation" hereinafter may also contribute to the changes in MAP signal characteristics over time by relieving the mechanical stresses caused by the electrode on the target cardiac tissue as well as by changing the electrical resistance of the tissue and the current path therethrough.
In an article titled "BASIC BIOPHYSICAL CHARACTERISTICS OF FRACTALLY-COATED ELECTRODES", by Bolz et al. published in "Monophasic Action Potentials", Franz, Schmitt and Zenner eds., pp. 40-57, Springer-Verlag, Berlin, 1997, the authors describe MAP-like signals recorded from near-term chronic implant of fractally-coated iridium electrodes. Signals resembling MAPs were recorded from such fractally-coated electrodes, 3 months after implantation. Unfortunately, MAP features are highly distorted in these recordings.
Furthermore, in a follow-up article by Zrenner et al., titled "RECORDING OF MONOPHASIC ACTION POTENTIALS WITH FRACTALLY-COATED ELECTRODES--EXPERIMENTAL AND INITIAL CLINICAL RESULTS", published in "Monophasic Action Potentials", Franz, Schmitt and Zenner eds., pp. 58-68, Springer-Verlag, Berlin, 1997, the authors report that in such chronic implants the mean MAP amplitude is decreased to less than 4 millivolts even in ventricular recordings, and that the morphology of the chronic MAP signal showed a depressed MAP plateau and a pronounced phase 3 repolarization resembling a T wave. The authors conclude that " . . . at present, the question of the feasibility of long-term recording and long-term stability of MAP remains unanswered".
Thus, unfortunately, current MAP recording techniques including, among others, use of plunge electrodes, suction electrodes, and pressure contact electrodes are not suitable for performing stable long-term chronic measurement of MAPs.